Human Genetics

, Volume 129, Issue 4, pp 397–405

Autosomal recessive hyponatremia due to isolated salt wasting in sweat associated with a mutation in the active site of Carbonic Anhydrase 12

  • Emad Muhammad
  • Neta Leventhal
  • Galit Parvari
  • Aaron Hanukoglu
  • Israel Hanukoglu
  • Vered Chalifa-Caspi
  • Yael Feinstein
  • Jenny Weinbrand
  • Harel Jacoby
  • Esther Manor
  • Tal Nagar
  • John C. Beck
  • Val C. Sheffield
  • Eli Hershkovitz
  • Ruti Parvari
Original Investigation

DOI: 10.1007/s00439-010-0930-4

Cite this article as:
Muhammad, E., Leventhal, N., Parvari, G. et al. Hum Genet (2011) 129: 397. doi:10.1007/s00439-010-0930-4

Abstract

Genetic disorders of excessive salt loss from sweat glands have been observed in pseudohypoaldosteronism type I (PHA) and cystic fibrosis that result from mutations in genes encoding epithelial Na+ channel (ENaC) subunits and the transmembrane conductance regulator (CFTR), respectively. We identified a novel autosomal recessive form of isolated salt wasting in sweat, which leads to severe infantile hyponatremic dehydration. Three affected individuals from a small Bedouin clan presented with failure to thrive, hyponatremic dehydration and hyperkalemia with isolated sweat salt wasting. Using positional cloning, we identified the association of a Glu143Lys mutation in carbonic anhydrase 12 (CA12) with the disease. Carbonic anhydrase is a zinc metalloenzyme that catalyzes the reversible hydration of carbon dioxide to form a bicarbonate anion and a proton. Glu143 in CA12 is essential for zinc coordination in this metalloenzyme and lowering of the protein–metal affinity reduces its catalytic activity. This is the first presentation of an isolated loss of salt from sweat gland mimicking PHA, associated with a mutation in the CA12 gene not previously implicated in human disorders. Our data demonstrate the importance of bicarbonate anion and proton production on salt concentration in sweat and its significance for sodium homeostasis.

Supplementary material

439_2010_930_MOESM1_ESM.tif (680 kb)
Family pedigree and haplotype analysis. The haplotype analysis based on microsatellite markers from 15q21.3-q23 revealed a founder haplotype (gray bar) for which the patients are homozygous in the critical region harboring the CA12 gene. The numbers of the patients correspond to those presented in Table 1.Patient II-3 was identified by analysis of the mutation. Filled symbols represent homozygote for the mutation and half filled symbols heterozygotes. The two lines indicate the crossing events delimiting the homozygous interval shared by all patients (TIF Image 681 KB)
439_2010_930_MOESM2_ESM.tif (1.6 mb)
Identification of the Glu143Lys Mutation in the CA12 gene at the Functionally Conserved Glu143 Amino Acid. a. Sequence of the genomic DNA corresponding c.583G>A mutation resulting in Glu143Lys. Patients were homozygous for the mutation, parents and siblings carrying the founder haplotype were heterozygous, and the healthy siblings without the founder haplotype were normal.b. Restriction analysis with Eco 130I enables to identify the mutation by cleavage of the mutated sequence. Normal- 600 bp PCR product of control. Homozygote presents 254bp and 346bp products of a patient. Heterozygote-presents 600bp, 254bp and 346bp products of a parent. At the left is marker X of Roche.c. Functional conservation of the replaced amino acid Glu143 mutated to Lys. The multiple sequence alignment, carried out by ClustalW represents the alignment of CA 12 to the 16 α-CA isozymes.The numbering relates to the positions of CAII, the best characterized enzyme, according to Whittington et al. (2001). Asterisk (*), identical; colon (:), strictly conserved (TIF Image 1,679 KB)

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Emad Muhammad
    • 1
  • Neta Leventhal
    • 2
    • 3
  • Galit Parvari
    • 4
  • Aaron Hanukoglu
    • 5
    • 6
  • Israel Hanukoglu
    • 7
  • Vered Chalifa-Caspi
    • 8
  • Yael Feinstein
    • 2
    • 3
  • Jenny Weinbrand
    • 2
    • 3
  • Harel Jacoby
    • 2
    • 3
  • Esther Manor
    • 1
    • 9
    • 10
  • Tal Nagar
    • 8
  • John C. Beck
    • 11
  • Val C. Sheffield
    • 11
  • Eli Hershkovitz
    • 2
    • 3
  • Ruti Parvari
    • 1
    • 8
  1. 1.Department of Virology and Developmental Genetics, Faculty of Health SciencesBen Gurion University of the NegevBeer ShevaIsrael
  2. 2.Pediatric Endocrinology and Metabolism UnitSoroka Medical CenterBeer ShevaIsrael
  3. 3.Faculty of Health SciencesBen Gurion University of the NegevBeer ShevaIsrael
  4. 4.Department of Organic and Inorganic Chemistry, Schulich Faculty of ChemistryTechnion-Israel Institute of TechnologyHaifaIsrael
  5. 5.Division of Pediatric EndocrinologyE Wolfson Medical CenterHolonIsrael
  6. 6.Tel Aviv University Sackler School of MedicineTel AvivIsrael
  7. 7.Department of Molecular BiologyAriel University CenterArielIsrael
  8. 8.National Institute of Biotechnology in the NegevBen Gurion University of the NegevBeer ShevaIsrael
  9. 9.Institute of GeneticsSoroka Medical CenterBeer ShevaIsrael
  10. 10.Faculty of Health SciencesBen Gurion University of the NegevBeer ShevaIsrael
  11. 11.Department of Pediatrics, Division of Medical Genetics, Howard Hughes Medical InstituteUniversity of IowaIowa CityUSA